The long-term objectives of this project are to determine the role of craniofacial sensory feedback in normal function and to determine how these processes are altered in oro-facial dysfunctions including bruxism, masticatory muscle and temporomandibular disorders. Three hypotheses are proposed: 1) Trigeminal ganglion jaw muscle and joint primary afferent neurons comprise two general categories with brainstem axonal projections correlated to their functional modalities. Hypothesis 1 will be tested by characterizing the physiological and morphological properties of these neurons using in vivo intracellular recording and staining. 2) Sensory feedback from non-spindle muscle and joint afferents is relayed directly to trigeminothalamic, trigeminohypothalamic, trigemino-parabrachial, trigeminospinal and trigeminal premotor neurons. These pathways are expected to convey discriminative, autonomic and emotional aspects of orofacial nociception; as well as innocuous proprioceptive and autonomic sensory feedback. Hypothesis 2 will be tested by characterizing neuronal circuitry from trigeminal ganglion muscle and joint afferents to brainstem neurons by combining in vivo retrograde and intracellular neuronal labeling. 3) Transmission from trigeminal ganglion neurons relaying feedback from muscle and joint to brainstem neurons can be modulated via presynaptic mechanisms. It is also predicted that primary afferent depolarization (PAD) and centrifugal action potentials can be evoked in these afferent axons which may induce neurogenic inflammation. Hypothesis 3 will be tested by determining if the anatomical substrate for presynaptic modulation of non-spindle muscle and jaw joint afferent terminals is present using intracellular labeling, confocal and electron microscopy. This hypothesis will also be tested by directly monitoring the membrane potential in primary afferent axons using in vivo intra-axonal recording during electrical and chemical stimulation of orofacial tissues. Mechanisms of PAD will be explored using GABAA and GABAB agonists and antagonists. Data from experiments in this proposal will provide better understanding of the morphology and physiology of deep orofacial primary afferent neurons and their brainstem circuitry. This knowledge will not only lead to a better understanding of brain mechanisms but is needed to develop rational treatment strategies for managing musculoskeletal and orofacial disorders. These data will also be used to investigate potential gender differences in the morphological substrate and physiological mechanisms of primary afferent neurons involved in musculoskeletal and orofacial disorders including musculoskeletal pain, temporomandibular disorders (TMD), fibromyalgia and myofacial pain.